Annexin - Structure

Structure

Several subfamilies of annexins have been identified based on structural and functional differences. However, all annexins share a common organizational theme that involves two distinct regions, an annexin core and an amino (N)-terminus. The annexin core is highly conserved across the annexin family and the N-terminus varies greatly. The variability of the N-terminus is a physical construct for variation between subfamilies of annexins.

The 310 amino acid annexin core has four annexin repeats, each composed of 5 alpha-helices. The exception is annexin A-VI that has two annexin core domains connected by a flexible linker. A-VI was produced via duplication and fusion of the genes for A-V and A-X and therefore will not be discussed in length. The four annexin repeats produce a curved protein and allow functional differences based on the structure of the curve. The concave side of the annexin core interacts with the N-terminus and cytosolic second messengers, while the convex side of the annexin contains calcium binding sites. Each annexin core contains one type II, also known as an annexin type, calcium binding site; these binding sites are the typical location of ionic membrane interactions. However, other methods of membrane connections are possible. For example, A-V exposes a tryptophan residue, upon calcium binding, which can interact with the hydrocarbon chains of the lipid bilayer.

The diverse structure of the N-terminus confers specificity to annexin intracellular signaling. In all annexins the N-terminus is thought to sit inside the concave side of the annexin core and folds separately from the rest of the protein. The structure of this region can be divided into two broad categories, short and long N-termini. A short N-terminus, as seen in A-III, can consist of 16 or less amino acids and travels along the concave protein core interacting via hydrogen bonds. Short N-termini are thought to stabilize the annexin complex in order to increase calcium binding and can be the sites for post-translational modifications. Long N-termini can contain up to 40 residues and have a more complex role in annexin signaling. For example, in A-I the N-terminus folds into an amphipathic alpha-helix and inserts into the protein core, displacing helix D of annexin repeat III. However, when calcium binds, the N-terminus is pushed from the annexin core by conformational changes within the protein. Therefore, the N-terminus can interact with other proteins, notably the S-100 protein family, and includes phosphorylation sites which allow for further signaling. A-II can also use its long N-terminal to form a heterotrimer between a S100 protein and two peripheral annexins. The structural diversity of annexins is the grounds for the functional range of these complex, intracellular messengers.